Given the recognition that "choosing appropriate thresholds[for serum natriuretic peptide] is problematic"(1), the best diagnostic strategy for obtaining maximum diagnostic "mileage" from natriuretic peptide levels might be that of interpreting any given result in the light of whether the patient has high, medium, or low clinical probability of heart failure. For that to come about, instead of reinforcing the idea that "Individual symptoms...and signs...are generally weak predictors of heart failure"(2), we should embrace the use of a scoring system such as the one recently compiled in the Netherlands which recognises the diagnostic value of physical examination by allocating points to individual clinical stigmata(3). We must also recognise that, as is the case with biomarkers(such as natriuretic peptides), even echocardiography is hedged in by caveats, not only in systolic heart failure(4), but also in diastolic heart failure(5). In the former context the redeeming feature is that, notwithstanding the fact that a subnormal left ventricular ejection fraction(LVEF) does not equate with clinically overt heart failure(6), in its own right, however, a subnormal LVEF does justify the use of modulators of the renin-angiotensin-aldosterone system(RAAS) such as angiotensin converting enzyme inhibitors(ACE-inhibitors) even if only to exert a favourable influence on the natural history of both subclinical and clinically overt heart failure(6). This means that, even if clinical symptoms and signs are not those of heart failure, ACE_inhibitors would still be justified in the event of a subnormal LVEF. A similar parallel does not exist for left ventricular diastolic dysfunction(when it does not co-exist with left ventricular systolic dysfunction) because there is no evidence base for justifying modulation of the RAAS through the use either of ACE inhibitors or spironolactone(or both) regardless of whether or not left ventricular diastolic dysfunction co-exists with symptoms attributable to heart failure. Accordingly, for patients with intact LVEF in whom echocardiographically validated left ventricular diastolic dysfunction coexists with "problematic" natriuretic peptide blood levels the central issue is whether or not associated clinical signs and symptoms signify clinical congestion and, hence heart failure, whether it be acute or chronic. Evidence-based parameters which have been utilised as criteria for clinical congestion include symptoms such as effort dyspnoea and orthopnoea, signs such as peripheral oedema, resting hugular venous distension, and the presence of a third heart sound, and radiographic stigmata such as cardiomegaly, pulmonary vascular redistribution, interstitial oeadema, and pleural effusion. All these have been evaluated for positive predictive value as well as for negative predictive value(7). We now need to optimise the accuracy of non-echocardiographic stigmata(3)(7) so as to respond constructively to the criticism levelled by a distinguished American physician at the "downplaying" of clinical evelaution in the NICE guidelines, when he said "Clinical evaluation is central to all complex clinical syndromes"(8), References (1)Al-Muhammad A., Mant J Republished technology and guidelines: The diagnosis and management of chronic heart failure: review following the publication of the NICE guidelines Postgrad Med J 2011;87:841-6 (2) Hobbs FDR., Doust J., Mant J., Cowie MR Diagnosis of heart failure in primary care Heart 2010;96:1773-7 (3) Kelder JC., Cramer MJ., van Wijngaarden J et al The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure Circulation 2011;124:2865-73 (4) Jolobe OMP Usefulness of left ventricular ejection fraction in patients with overt heart failure(letter) Mayo Clinic Proceedings 2006;81:1636-9 (5)Paulus WJ., Tschope C., Sanderson JE et al How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Haert Failure and Echocardiography Association of the European Society of Cardiology Eur Heart J 2007;28:1539-50 (6)The SOLVD Investigators Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions N Engl J Med 1992;327:685-91 (7)Gheorghiade M., Follath F., Ponikowski P et al Assessing and grading congestion in acute heart failure: A scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine European Journal of Heart Failuer 2010;12;423-33 (8) Finucane TE NICE Guideline for Management of Chronic Heart Failure in Adults(letter) Annals of Inernal Medicine 2012;156:69

Conflict of Interest:

None declared

Notwithstanding the absence of robust evidence to justify the use of antipyretic analgesics either for reducing patient discomfort or for reducing morbidity and mortality in febrile illnesses(1), it is only in recent times(2)(3) that the issue of drug-related mortality has been adressed in patients receiving either nonsteroidal anti-inflammatory drugs(NSAIDs) or paracetamol for febrile illnesses. Due to insensible losses via the skin and also via the respiratory tract, patients with pneumonia seem to be uniquely predisposed to NSAID-related nephrotoxicity, as was the case in a five year old girl who received recommended doses of ibuprofen(presumably for its antipyretic action) over a period of 4 days before she developed acute renal failure, characterised by peak serum creatinine 171 mcmol/l, and peak serum urea 23 mmol/l. Following the discontinuation of ibuprofen these parameters took 3 days to revert to the normal range(4). Both hepatitis and non-oliguric renal failure were the cardinal complications of the administration of paracetamol, followed by ibuprofen, in a 5 year old girl with febrile convulsions and vomiting. The former was prescribed as 11 mg/kg/dose, two total doses, over 5 hours. This was followed by ibuprofen 5 mg/kg/dose every 8 hours, three total doses. Both drugs were administered by mouth. Although her renal function tests and liver function tests had been within the normal range on admisssion, on day six aspartate transaminase and gammaglutamyl transaminase had increased to 144 iu/l, and 1394 iu/l, respectively. Correspondigly, serum urea and serum creatinine had increased to 67.9 mg/dl and 6.34 mg/dl, respectively. By day 60 all the abnormal parameters had reverted to the normal range(5). In the non febrile context, recommended doses of paracetamol administerd to adult patients over a period of 4-5 days, have been documented as being the cause of acute liver failure(6). Accordingly, especially in the context of febrile illnesses where insensible loss of fluid via the skin is compouded by fluid loss via the respiratory tract(as in pneumonia)(4) or compouded by fluid loss via the gastrointestinal tract as in the second case(5), there should be a high index of suspicion for subsequent development of renal failure. Where paracetamol is administered to patients with poor nutritional status, clinicians should be alert to the risk of drug-related hepatotoxicity(6) References (1) Greisman L., Mackowiak PA Fever: beneficial and detrimental effects of antipyretics Current Opinion in Infectious Diseases 2002;15:241-5 (2) Plaisance Toxicities of drugs used in the management of fever Clinical Infectious Diseases 2000;31(Suppl 5): S219-23 (3)Jefferies S., Weatherall M., Young P., Eyers S., Beasley R Ssystematic review and meta analysis of the effects of antipyretic medications on mortality in Streptococcus Pneumoniae infections Postgraduate Medical Journal 2012;88:21-27 (4)Ulinski T., Guigonis V., Dunan O., Bensman A Acute renal failure after treatment with nonsteroidal antiinflammatory drugs Eur J Pediatr 2004;163:148-150 (5) Zaffanello M., Brugnara M., Angeli S., Cuzzolin L Acute non-oliguric kidney failure and cholestatic hepatitis induced by ibuprofen and acetoaminophen: a case report Acta Paediatrica 2009;96:901-9 (6)Claridge LC., Eksteen B., Smith A., Shah T., Holt AP Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults BMJ 2010;341:1269-1271

Conflict of Interest:

None declared

Management of special type of dyslipidemia; Low HDL-C, high TG, Type- B size LDL-P in patients with T2DM is a big challenge for a physician. For primary LDL-C goal, we the physician usually go for stronger statins like atorvastatin or rosuvastatin. Addition of fenofibrate to the above statins to reduce concomitant high TG really reduces TG level but does such combination offer any strong role in reducing mortality in this population [1]? To increase HDL-C, trials with CETP inhibitors like torcetrapib or anacetrapib failed to reduce CV mortality. Newer CETP inhibitor evacetrapib although leading to increase HDL-C but cardiovascular protection is still under question [2]. We were using extended release nicotinic acid along with statin (ARBITER 6 -HALTS trial) but my practice did not show any significant benefit. Recently, after premature halting of AIM-HIGH trial, efficacy of nicotinic acid also became under question and even increased events of ischemic stroke in this population leading me to change my treatment strategy. Currently no safe drug to increase HDL-C is available. More ever, drug induced increased HDL has no CV benefit. Lifestyle modification is still remaining the best strategy along with statin and if necessary, n-3 to manage dyslipidemia in patients with diabetes and other high risk population.

Ref: 1. Hyperlipidaemia and cardiovascular disease: do fibrates have a role? Current Opinion in Lipidology: August 2011 - Volume 22 - Issue 4 - p 270-276 doi: 10.1097/MOL.0b013e32834701c3 2. Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol. JAMA.2011;306(19):2099-2109. doi:10.1001/jama.2011.1649

Conflict of Interest:

None declared

Reply to Reply In reply to De Wets and Bowie's reply to my criticism:

De Wet and Bowie state 1. Our paper makes it very clear that this is a study of primary care records and not of consultations, GPs or of primary care per se.

Reply Although this is true, nowhere does the paper explicitly explain that is looking in primary records for errors across the totality of healthcare. This is not mentioned until page 179 (4th page of article) and then only in passing. The clear assumption is that this is a study of primary care records and is looking for error and harm in primary care and this impression is not overtly refuted in the article.

De Wet and Bowie state 3. The harm rate per number of records and consultations is provided to make the results more meaningful for primary care clinicians who have multiple patient contacts.

Reply No primary care clinician I have spoken to thinks including secondary care events makes the results more meaningful to primary care clinicians. Primary care clinicians want to know what their own error/harm rate is. They do not want secondary care error/harm rates added to their own figures and inflating the 'primary care' error/harm rate.

De Wet and Bowie state 4. Johnstone suggests the harm rate should be expressed as '...47 per 2251 consultations (2.1%)...' We provided this measure i.e. 1 per 48 consultations (a ratio that equates to 2.1%). We could calculate at least six different measures involving the following variables: error, harm, preventability, setting, record and consultation. All provide useful but limited information, none is superior. We focused on harm per record because that is what we judged as most relevant to patient safety.

Reply I have no problem with this, but it must be made explicit and this is not the case in this paper. The paper does not explicitly state that secondary care errors are being included. Spinal surgery errors are mentioned in passing and on page 179 the paper mentions 'procedures in secondary care.' The paper continually mentions primary care, using the tool to provide a 'primary care equivalent'. On page 2 the paper's aims are to 'test a validated trigger tool for the primary-car setting'. It does not mention a secondary care setting. This lack of clarity invalidates this paper.

De Wet and Bowie state 5. We detected harm that originated in secondary care, which concurs with previous research. (4) We discuss the implications of this and that most 'severe' cases originated in this setting. We do not state that the harm rate of 9.4% is "for" primary care but make it clear that it is the harm rate found in the records, regardless of source of origin or preventability judgements.

Reply Although De Wet and Bowie mention secondary care once in the discussion section on page 179, the rest of the paper talks about harm and error in primary care. The whole paper is about using the trigger tool to detect and quantify error and harm in primary care, not in secondary care.

De Wet and Bowie state 6. Definitions of error and adverse event are outlined in our Methods section. Careful reading of Tables 3 and 4 shows that matching study data are presented for each category using the NCCMERP Error Index employed (which defines near misses, error and harm). We use harm and adverse event interchangeably, which is accepted practice. (5)(6)(7)

Reply I accept this, but harm is regularly used when error should be used. This occurs in the titles of tables 3 and 4. The NCCMERP tool detects error, not just harm, not all errors lead to harm and not all harm is due to error. This suggestsharm is more common than it is. On page 179 is the sentence Most cases of harm were graded as category A-E (temporary harm to a patient requiring an intervention). This is inaccurate as only category E is harm, categories A-D are errors with the potential for harm, but with no actual harm occurring.

De Wet and Bowie state 7. The NCCMERP index was selected in the absence of a universally agreed system and because it is used in hospital care. We did not adapt it to reduce bias. We provide a rationale: "In secondary-care studies, only categories E to I have been used, as they correlate with actual patient harm occurring. We included all categories because we assumed that relatively minor events may be more common in primary care". This assumption was proved correct. We also made the following recommendation: "It may be reasonable to use only categories E to I in future to target patient harm rather than just error".

Reply De Wet and Bowie have misread their own paper, on page 180 they state ' Few adverse events were in categories A-D despite the expectation of high error incidence.' Their assumption was proven wrong not correct.

De Wet and Bowie state 8. Johnstone states that he "almost believes" that we "confuse" these terms "on purpose". This comment is lacking in reason and evidence.

Reply True

De Wet and Bowie state 10. Johnstone queries the category E harm example in Table 2 (refer also to our No. 6 and 7 responses). Some harm events may arise from normal or evidence-based care. There may be no associated error (as in this example) or obvious error. To illustrate: a patient is appropriately prescribed an antibiotic but develops an allergic reaction. Record review reveals a similar prescription and outcome previously, but no allergy code was added. Arguably, this is preventable harm.(9)

Reply I agree, the second prescription is preventable harm, the first prescription is unavoidable harm.

De Wet and Bowie state 11. Johnstone is factually incorrect in stating that of "...the 47 events in primary care, 11 were in the range of possible harm rather than actual harm". 47 records contained evidence of some harm i.e. categories E (n=39), F (n=6) and G (n=2). We cannot make this clearer.

reply Yet again De Wet and Bowie have misread their own paper and confused primary and secondary care. There are 47 events in primary care and 11 are the category A-D, therefore possible harm not actual harm. Co-incidentally the number of events in categories E-G is also 47, but 11 of these occurred in secondary care.

De Wet and Bowie state 12. Johnstone states that we make a "throwaway comment" in the opening paragraph because we suggest that the evidence cited is "...likely to be an underestimation". Based on the evidence in hospital care (10), we hypothesised that the rate in primary care is greater than currently suggested, which is standard research practice. Our findings support our hypothesis.

Reply I disagree, De Wet and Bowie's findings show that preventable harm in primary care is 1:125 consultations, almost identical to 1:120 consultations which they thought was an underestimation.

De Wet and Bowie state 14. The issue over the "headline figure" being "inflated" from 9.4% to 9.5% (it was rounded to the nearest 0.5%) is external to the debate on the published paper.

Reply Point taken, I will follow this up separately.

De Wet and Bowie state 17. We did not exclude the records of the 94 patients (18.8%) who had no contact with primary care in the 12-month study period. If we now exclude them (which is reasonable), the actual harm rate is 47/406 (11.6%), strongly suggesting we underestimated the 'true' level.

Reply The rate of preventable harm in 1:125 consultations is unaffected whether the these 94 patients are included or excluded.

De Wet and Bowie state 18. We concede that our Abstract should read "...27/64 (42%) of error and harm events were judged preventable..." However, this issue is reported clearly in the main paper.

De Wet and Bowie state 19. We cannot control how others interpret our findings and are always careful to explain the scientific limitations of our study.

Reply Fair point, but the authors can control how the authors interpret and explain their study. This is not directly related to retracting this paper but on 10th June Bowie gave a power-point presentation titled 'Patient Safety and the GPST' . The presentation states 'The NES Trigger Tool... may enable you to measure the preventable harm rate.. which you can monitor and reduce overtime.' Although they include secondary events, it is hard for primary care clinicians to reduce errors in secondary care, eg pain after a spinal operation. Had De Wet and Bowie applied this sentence to their own paper, they would have reported the preventable harm rate in primary care as 0.8% not 9.4%

De Wet and Bowie state Screening medical records for undetected harm events only provides a single perspective. The process cannot capture 'acts of omission' that lead to harm nor are findings likely to correlate with data from patients, incident reporting systems, significant event analyses, complaints, litigation claims and so on. (11)(12)(13) The patient safety problem is highly likely to be greater than can be deduced from screening medical records, even when we account for source of origin and preventability judgements.

Reply I agree that Patient Safety is a major issue and should be taken immensely seriously. However I do not believe it helps anyone to portray the problem as greater than it is. I believe this paper has inaccuracies and gives the impression of a 9.4% harm rate in primary care when the actual figure could be better described as preventable harm occurs in 1:125 consultations in primary care (0.8%).

Conflict of Interest:

None declared